Transcriptional silencing via promoter methylation of genes critically important for cell growth and differentiation plays a key role in myeloid leukemogenesis. Many genes are frequently methylated in acute myeloid leukemia (AML) including p15, estrogen receptor (ER), and calcitonin, among others.[1- 4] A promising drug in the treatment of AML and other myeloid disorders is the DNA methyltransferase inhibitor (DNMT) inhibitor decitabine, 5-aza-2'-deoxycytidine.[5-10] Decitabine has significant activity in AML and myelodysplastic syndrome (MDS) when given at low doses (and repetitive cycles) which favor demethylating activity, rather than cytotoxicity. We have published results of a phase I study of decitabine in AML[11] which determined an optimal daily dose of decitabine at 20mg/m2/day based on re-expression of epigenetically silenced genes. Re-expression of ER, detected early in cycle 1 of therapy, correlated with subsequent achievement of response (CR/CRi). In June 2008, we completed enrollment (N=33) of a phase II study of single agent decitabine in previously untreated AML patients age >60 years who were not candidates for intensive therapy. Decitabine was given at 20mg/m2/day for 10 days/cycle during induction and for 5 days/cycle during post-remission therapy. To date, the CR rate by IWG criteria[12] on this study is 42% (14/33);the CR+CRi rate is 58% (19/33). The approach has reduced toxicity relative to standard cytotoxic therapy and remissions appear durable (2-13 months to date). The maintenance schedule is well tolerated even by older and infirm AML patients. On the basis of these promising clinical and pharmacodynamic results, and with the support of the Cancer and Leukemia Group B (CALGB), we have moved this active agent into a comprehensive first line treatment plan for younger patients (age <60) with newly diagnosed AML. We designed a study of maintenance therapy with decitabine for one year, for AML patients who remain in first remission after completing an established induction and intensification regimen (CALGB 10503). The specific aims of the study are the following: 1) To determine 1 year disease free survival (DFS), feasibility, and toxicities of one year of maintenance decitabine given to patients <60 years with newly diagnosed, untreated AML who achieve and maintain first remission following an established induction and intensification regimen (compared to a benchmark historical control of patients treated with the same regimens in the CALGB previously) and 2) To determine the prognostic value (at diagnosis and remission, respectively) of methylation-specific markers of AML such as global DNA methylation and target gene- specific aberrant promoter hypermethylation, and the impact of decitabine maintenance therapy on modulation of these and other markers of minimal residual disease (MRD). PUBLIC HEALTH RELEVANCE: We propose adding low dose, outpatient decitabine treatment for younger patients who remain in remission after intensive chemotherapy for AML. It is hoped that decitabine will wipe out the remnants of leukemia that may be leftover after completion of chemotherapy (called minimal residual disease) and thus help to prevent relapse of AML. Important to the success of the project are the development of new tests to predict outcomes in AML and new methods to detect minimal residual disease in patients who are in remission. We hope to more accurately predict response to treatment and assess risk of relapse.